Featured Research

from universities, journals, and other organizations

Oral Delivery System For RNAi Therapeutics

Date:

May 5, 2009

Source:

University of Massachusetts Medical School

Summary:

Researchers have developed a novel approach to the delivery of small bits of genetic material in order to silence genes using "RNA interference" -- and in the process, discovered a potent method of suppressing inflammation in mice similar to what occurs in a range of human diseases.

Share This

Researchers at the University of Massachusetts Medical School (UMMS) report April 28 on a novel approach to the delivery of small bits of genetic material in order to silence genes using "RNA interference"—and in the process, discovered a potent method of suppressing inflammation in mice similar to what occurs in a range of human diseases.

Related Articles

In the April 30, 2009 issue of the journal Nature, Professor Michael P. Czech, PhD, and colleagues in the Program in Molecular Medicine at UMMS describe the engineering of small encapsulating particles containing short pieces of RNA that dramatically silenced genes in mice following oral administration in small doses. The article provides a possible pathway to address the most common—and daunting—challenge in the new field of RNA therapeutics: how to deliver the short strands of RNA used in gene silencing to specific tissues and cell types.

"We are very encouraged by these results, which show that oral delivery of a therapeutic dose of small, interfering RNA (siRNA) to a specific cell type in an animal model is possible, and that evidence of gene silencing using this delivery system is measurable," said Dr. Czech.

The discovery in 1998 that short strands of RNA can silence the action of a given gene changed the scientific world's understanding of how genes are regulated. Highly specific and highly potent, "RNA interference" or "RNAi" has become both a crucial laboratory technique and widely studied for potential therapeutic applications; the explanation of the mechanism of RNAi was recognized with the 2006 Nobel Prize in Medicine, awarded to UMMS Professor Craig C. Mello, PhD, and collaborator Andrew Z. Fire, PhD, of Stanford University; since the discovery, laboratories around the world have focused on the potential of RNAi to silence genes with high specificity, low toxicity and minimal immune system response.

But how to deliver tiny strands of genetic material into cells in a living organism has been a formidable obstacle. In this paper, Czech and colleagues chose to target a particular type of cell in the immune system called a "macrophage," a type of white blood cell that engulfs and digests cellular debris and responds to invading organisms by stimulating the immune response. Because macrophages control the inflammatory response in diseases such as rheumatoid arthritis and atherosclerosis (a precursor to heart disease), they represent an attractive target for drug delivery.

To move short strands of RNA into the macrophages, the researchers exploited a distinctive characteristic of yeast particles: the ability to be engulfed and digested by macrophages. By using these yeast particles as a delivery shell, they were able to deliver siRNAs targeting a gene known for its key role in the inflammatory response—and turn it off. The macrophages carrying the RNAi moved throughout the organism as they circulated from the digestive system (where they first encountered the particles and engulfed them) with the result that over time, a large portion of the organism's macrophages exhibited gene silencing.

The method of treating yeast particles to remove components that would cause an immune response and generate oral delivery vehicles composed of "beta1,3-D glucan" was developed by UMMS research professor and paper co-author Gary R. Ostroff, PhD. The method of using glucan particles as a drug delivery system has been tested in a number of animal models. In December 2008, the Massachusetts Life Sciences Center awarded a three-year, $750,000 cooperative research grant to UMMS and biotech startup RXi Pharmaceuticals to investigate the development of a range of orally delivered RNAi therapeutics using the glucan particle model. (RXi was co-founded by Nobel Laureate Mello, who serves on its Scientific Advisory Board, and Czech.)

In the series of experiments, the researchers were able to silence gene expression both in vitro and in vivo, in a mouse model, at a range of doses and concentrations; oral delivery of as little as 20 micrograms per kilogram of body weight of siRNA silenced a signaling protein called MAP4K4, a key player in the inflammatory response in disease processes like arthritis. (By contrast, research studies evaluating intravenous injections of siRNAs often used concentrations from 12 to 500 times higher.)

"In the future, this paper will be viewed as a landmark in the process of translating RNAi into effective new therapies for human diseases," said Terence R. Flotte, MD, dean of the school of medicine at UMMS. "It addresses one of the most fundamental problems in the field, that of delivery of the RNAi molecule to the cells affected by the disease process."

University of Massachusetts Medical School. (2009, May 5). Oral Delivery System For RNAi Therapeutics. ScienceDaily. Retrieved March 31, 2015 from www.sciencedaily.com/releases/2009/04/090429132236.htm

Mar. 31, 2015  Increasing state alcohol taxes could prevent thousands of deaths a year from car crashes, say researchers, who found alcohol-related motor vehicle crashes decreased after taxes on beer, wine and ... full story

Mar. 31, 2015  Alcoholism takes a toll on every aspect of a person's life, including skin problems. Now, a new research report helps explain why this happens and what might be done to address it. "The clinical ... full story

Mar. 31, 2015  A new population of 'memory' immune cells has been discovered by scientists, throwing light on what the body does when it sees a microbe for the second time. This insight, and others like it, will ... full story

Mar. 31, 2015  Coronary heart disease and stroke, two of the leading causes of death in the United States, are diseases associated with heightened platelet reactivity. A new study in humans suggests an underlying ... full story

Mar. 31, 2015  A new study had researchers seeking answers to why the therapeutic benefit afforded by SSRIs was so limited in children and teenagers. If researchers can uncover the biological mechanisms preventing ... full story

Mar. 31, 2015  A drug being developed to treat osteoporosis may also be useful for treating osteogenesis imperfecta or brittle bone disease, a rare but potentially debilitating bone disorder that that is present ... full story

Mar. 31, 2015  It is possible to quantify and classify the effects of different diseases on the activity of intestinal bacteria, new research demonstrates for the first time. Human intestinal flora, known as ... full story

Mar. 31, 2015  During prenatal development, the brains of most animals, including humans, develop specifically male or female characteristics. But scientists have known little about the details of how this ... full story

Mar. 31, 2015  A history of depression may put women at risk for developing diabetes during pregnancy, according to research. This study also pointed to how common depression is during pregnancy and the need for ... full story

Featured Videos

Solitair Device Aims to Takes Guesswork out of Sun Safety

Reuters - Innovations Video Online (Mar. 31, 2015)  The Solitair device aims to take the confusion out of how much sunlight we should expose our skin to. Small enough to be worn as a tie or hair clip, it monitors the user&apos;s sun exposure by taking into account their skin pigment, location and schedule. Matthew Stock reports.
Video provided by Reuters

Soda, Salt and Sugar: The Next Generation of Taxes

Washington Post (Mar. 30, 2015)  Denisa Livingston, a health advocate for the Dinι Community Advocacy Alliance, and the Post&apos;s Abby Phillip discuss efforts around the country to make unhealthy food choices hurt your wallet as much as your waistline.
Video provided by Washington Post

S. Leone in New Anti-Ebola Lockdown

AFP (Mar. 28, 2015)  Sierra Leone imposed a three-day nationwide lockdown Friday for the second time in six months in a bid to prevent a resurgence of the deadly Ebola virus. Duration: 01:17
Video provided by AFP

Nov. 13, 2014  A new approach to block the KRAS oncogene, one of the most frequently mutated genes in human cancer, has been developed by researchers. The approach offers another route to attack KRAS, which has ... full story

May 12, 2014  RNA carried by new nanoparticles can silence genes in many organs, and could be deployed to treat cancer, researchers report. Up to this point, researchers have gotten the best results with RNAi ... full story

Oct. 3, 2013  A research team has discovered the mechanism by which an aggressive fungal pathogen infects almost all fruits and vegetables. The team discovered a novel virulence mechanism of Botrytis cinerea, a ... full story

Feb. 24, 2011  Scientists have developed a powerful method that allows them to sift through thousands of candidate hairpin-shaped RNA molecules at a time and pull out only those RNAs that potently shut down the ... full story

ScienceDaily features breaking news and videos about the latest discoveries in health, technology, the environment, and more -- from major news services and leading universities, scientific journals, and research organizations.